Virtual elimination of vertical transmission of HIV is within reach in South Africa. Despite high antenatal HIV prevalence, implementation of currently available technology and guidelines in the South African Prevention of Mother-to-Child Transmission (PMTCT) program, and particularly the longstanding and comprehensive program in the Western Cape Province, South Africa, has resulted in substantial reductions in vertically transmitted HIV to 3.5% across the country, and 3.3% in the Western Cape. Yet, elimination remains elusive due to persistent coverage gaps and drop-offs at each of the steps required in completion of the PMTCT and infant care continuum, with upwards of 1000 vertically infected infants born in the Western Cape each year. Improving the performance of the current PMTCT and antiretroviral therapy (ART) guidelines at each point in the care continuum through meticulous surveillance of system failures with resultant intervention, are key to further mitigating the effect of HIV on children, irrespective of possible future introduction of different guideline and service design options. Strengthening the health system with this active surveillance approach will provide long term benefits that will both complement and endure beyond future changes in drug protocols or service delivery models. This system will foster a paradigm in which identified cases of infant HIV exposure not covered by PMTCT drugs and HIV infected infants are viewed as a public health emergency requiring urgent intervention to identify reasons for program failure and mitigate its effects in an individual child. This project focused on a primary care obstetric facility, aims to implement and evaluate three linked enhancements to the existing service platform that will iteratively identify and close all PMTCT and early infant diagnosis and ART coverage gaps. First, existing paper registers at antenatal, obstetric and infant clinics will be digitized, internally linked, and merged with laboratory data using context-appropriate technology that has been applied to other priority programs, namely ART and TB monitoring. The combined PMTCT e-register will be linked to a system of urgent reporting of laboratory results of low CD4 counts in pregnant women and positive infant HIV-PCR test results to clinics, with tracing to ensure prompt ART initiation. This will strengthen the health system to close these key PMTCT coverage gaps. Second, a system of routine cord blood testing for HIV, and, if positive, the presence of antiretroviral drugs (ARVs) will identify and link to care HIV-exposed infants with no/suboptimal peripartum ARVs to ensure interventions to prevent postnatal transmission, prompt infant diagnosis and ART if infected. Third, a program of clinical quality assurance, improvement and audit will be established. This will be based on data from both the e-register and cord blood surveillance that will generate an early warning system of coverage gaps. Using these data, PMTCT program failures will be regularly and systematically analyzed together with Provincial and Local Departments of Health service managers and providers, with a view to achieving iterative service improvements. PUBLIC HEALTH RELEVANCE: Virtual elimination of pediatric HIV, the leading cause of under 5 mortality in South Africa, is possible with current PMTCT technology and guidelines, but remains elusive due to persistent coverage gaps and missed opportunities for PMTCT, despite a longstanding and comprehensive program. Systems to strengthen and enhance the effectiveness of health service implementation of PMTCT are therefore needed. The goal of this project is to implement and evaluate a replicable active surveillance system integrated with the existing monitoring platform that aims to (i) provide an early warning system of PMTCT coverage gaps leading to iterative program performance improvements and (ii) identify and link to care pregnant women and HIV exposed and infected infants critically needing ART or interventions to prevent transmission, thus closing key gaps in the PMTCT continuum.